Alzheimer's disease (AD) is the most common form of age-related dementia, affecting millions of persons worldwide and presenting a significant burden to healthcare systems. Pathological hallmarks of the disease are the deposition of beta amyloid (fA2) protein as insoluble, extracellular fibrillar amyloid plaques in the brain parenchyma and intraneuronal accumulation of hyperphosphorylated tau. Microglia, the brain's tissue resident macrophage, mount a proinflammatory immune response against A2 plaques. Microglia recognize A2 plaques through the toll-like receptors (TLRs). TLRs orchestrate the proinflammatory state through the interleukin-1 receptor-associated kinases (IRAKs). However, microglia can exist in different states of activation that have different physiological consequences. Furthermore, transition between these states can also influence their pro or anti-inflammatory characteristics. Loss of the kinase activity of the signaling molecule IRAK4 blocks the ability of macrophages to adopt a classical activation state. The hypothesis driving this work is that the activation state of microglia in Alzheimer's disease has a direct impact on disease pathogenesis and that a switch between activation state occurs during disease progression. One specific goal of this proposal is to test if loss of IRAK4 kinase activity decreases amyloid pathology in a mouse model of Alzheimer's disease. This will be achieved by crossing IRAK4 kinase-dead mice with a mouse model of AD. Animals will be assessed at various time points during disease for markers of microglial activation such as TNF1 and Arginase1. AD pathology will be evaluated through analysis of A2 levels and plaque burden. A second specific goal of this proposal is to determine if loss of IRAK4 kinase activity alters the activation status of microglia and their response to amyloid fibrils. Microglia from WT and IRAK4 KD mice will be primed to an alternative activation status with IL-4 and then presented with fA2. Their activation status will be monitored through cytokine measurements and NF:B activation status. Further, activation of signaling pathways such as p38 and Jnk, which are involved in classical activation and upregulated in AD, will be assessed through biochemical methods. By characterizing the role that activation status of microglia plays in AD pathogenesis, more effective future therapeutic interventions will be able to be developed. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a chronic neurodegenerative disease that affects millions of persons. This project addresses the role that the immune system plays in Alzheimer's disease. A better understanding of the immune response in Alzheimer's disease will lead to more effective treatments.